Diabetic retinopathy (DR) is the leading cause of blindness in working-age adults in industrialized countries, and its effects on public health will become even greater because of the rising incidence of diabetes world-wide. Visual impairment in diabetic retinopathy results from two causes: increased retinal vascular permeability (which leads to diabetic macular edema) and capillary drop-out (which leads to retinal ischemia/hypoxia and the subsequent development of retinal neovascularization). Diabetes creates oxidative stress and pro-inflammatory changes in the retina, which are critical for the pathogenesis of diabetic retinopathy. As a result, the regulation of these processes is important for the progression of DR. The transcription factor Nrf2 has an important cytoprotective role against oxidative stress and inflammation in multiple disease processes. Nrf2 is quite amenable to pharmacologic modulation, so its protective effects can be augmented. Our lab has been studying the role of Nrf2 in the retina. We have found that the Nrf2 system plays a vital protective role in the retinal response to ischemia-reperfusion injury. Furthermore, we have preliminary evidence that Nrf2 plays an important role in diabetic retinopathy. We hypothesize that Nrf2 is an important protective mechanism regulating oxidative stress and pro-inflammatory changes in the retina in diabetes. We further hypothesize that Nrf2 regulates vascular permeability and capillary dropout in diabetic retinopathy and propose the following 3 aims: Specific Aim 1. Determine the role of Nrf2 in the regulation of oxidative stress and pro-inflammatory processes in a diabetic mouse model. Specific Aim 2. Determine the role of Nrf2 on vascular permeability and capillary drop-out in a diabetic mouse model. Specific Aim 3. Determine if pharmacologic activation of Nrf2 protects against pathophysiologic and functional changes in diabetic retinopathy. We anticipate that these aims will allow us to implicate Nrf2 as an important protective mechanism in diabetic retinopathy and provide a new therapeutic strategy for this sight-threatening condition. PUBLIC HEALTH RELEVANCE: Diabetic retinopathy (DR) is the leading cause of blindness in working-age adults in industrialized countries, and its effects on public health will become even greater because of the rising incidence of diabetes world-wide. This research will allow us to determine the role of the protective molecule Nrf2 in regulating diabetic retinopathy. This could allow us to develop a new therapy for this sight-threatening condition, aimed at augmenting the protective effect of Nrf2.